119th General Meeting of the KCS

Type Oral Presentation
Area Bioconjugation
Room No. 403호
Time THU 09:20-:
Code BIO.O-3
Subject Development of a Stapled Peptide Inhibitor Targeting NCoA1/STAT6 Interaction
Authors 이영주, 임현석*
POSTECH 화학과, Korea
Abstract Signal transducer and activator of transcription 6 (STAT 6) is a member of STAT family. It takes a critical role in immune response that involves in IL-4/IL-13 signaling after the binding with the essential coactivator NCoA1. However, abnormally activated STAT6 can increase inflammation signaling and lead to disease such as asthma. The conventional approaches to decrease inflammation signaling were to block either IL-4/IL-13 signaling factor. Instead, we focused on the NCoA1/STAT6 interaction which can block both IL-4/IL-13 signaling. The interaction between NCoA1 and STAT6 is mediated by LXXLL motif which acts as alpha helix recognition motif. Here in, we developed series of compounds that mimic the helical region of STAT6 protein by adopting ring closing metathesis method with Grubb's catalyst and Dibromo-xylene stapling method to inhibit the NCoA1/STAT6 interaction. Among these compounds, SS2 provides 10 times increased binding affinity compared to the non-stapled native peptide. In addition, it has much improved serum stability and cell permeability. SS2 disrupts NCoA1/STAT6 interaction in cellular level and decrease the transcriptional activity mediated by STAT6. In this study, we discovered the first-in-class NCoA1/STAT6 inhibitor that binds to NCoA1 competitively and disrupts NCoA1/STAT6 interaction. We expect that SS2 can be an effective NCoA1/STAT6 interaction inhibitor, and can further be a potential therapeutic candidate.
E-mail lyj0308@postech.ac.kr